Successful therapeutic application of stem cells for tissue regeneration or gene delivery will require a sufficient pool of cells capable of long-term engraftment and functionality. Therefore, expansion of stem cell population and their differentiated progeny represent a fundamental hurdle to their therapeutic efficacy. Human embryonic stem cell (hES) research offers great promise in regenerative medicine since the first hES cell line was established in 1998. Like mouse embryonic stem (mES) cells, hES cells appear pluripotent or totipotent, thereby offering an indispensable source of cells for tissue regeneration or repair and also an extremely powerful biological tool for studying human diseases. Unlike mES cells, however, current efforts towards culture and manipulation have been hampered by their limited proliferation in vitro. Previous reports have indicated a role for the cyclin-dependent kinase inhibitors p18, p21, and p27 in regulating stem cell proliferation. Further investigation of the cell cycle status and determination of the role cyclin-dependent kinase inhibitors play in governing hES, will permit targeted strategies to increase their proliferation in vitro, thereby enhancing their study and future therapeutic applications. Despite the supportive data in mES cells, the mechanism governing hES cell proliferation could be entirely different. Strengths fo th [unreadable] [unreadable] [unreadable]